The alkaloids obtainable from Vinca rosea represent one of the most productive areas of chemistry for drugs which adversely affect the growth of experimental malignancies in mammals. Initially, only some of the alkaloids obtainable from the leaves of the plant by extraction and purifiable by chromatography were found to be active. These active anti-neoplastic vinca alkaloids obtained directly from the plant have been found to be dimeric indole-dihydroindole alkaloids representable by the formula: ##STR1##
In the above formula where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vinblastine (vincaleucoblastine, VLB) is represented; where R.sup.1 is acetoxy, R.sup.2 is formyl, R.sup.3 is hydroxyl, R.sup.4 is ethyl and R.sup.5 is H, vincristine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl, R.sup.3 is ethyl, R.sup.4 is hydroxyl, and R.sup.5 is H, leurosidine is represented; where R.sup.1 is acetoxy, R.sup.2 is methyl or formyl, R.sup.3 is ethyl and R.sup.4 and R.sup.5 taken together form an .alpha.-epoxide ring, leurosine and leuroformine, respectively are represented. Literature references to the above alkaloids are as follows: leurosine (U.S. Pat. No. 3,370,057), VLB (U.S. Pat. No. 3,097,137), leuroformine (Belgian Pat. No. 811,110); leurosidine (vinrosidine) and leurocristine (to be referred to hereafter as vincristine) (both in U.S. Pat. No. 3,205,220).
Two of the above alkaloids, vinblastine and vincristine, are now marketed for the treatment of malignancies, particularly the leukemias and related diseases, in humans. The two marketed alkaloids are customarily administered by the iv route. Two others, leurosidine and leuroformine, have been on clinical trial in the U.S. or in Europe.
Chemical modification of the Vinca alkaloids started slowly for several reasons. In the first place, the molecular structures involved are extremely complex, and chemical reactions which modify one specific functional group of the molecule without affecting other groups have been difficult to develop. Secondly, dimeric alkaloids lacking desirable chemotherapeutic properties have been recovered or produced from Vinca rosea extracts, and a determination of their structures has led to the conclusion that these inactive compounds are closely related structurally to, or even isomeric with, the active alkaloids.
One of the more recent, and more successful, modifications of the basic indole-dihydroindole structure has been the preparation of C-3 carboxamide and carboxhydrazide derivatives. Many of these carboxamides are active anti-tumor agents (see U.S. Pat. No. 4,166,810, and Conrad et al., J. Med. Chem., 22, 391 (1979). In particular, 4-desacetyl VLB C-3 carboxamide (vindesine) is very active and is currently on clinical trial in humans.
U.S. Pat. No. 4,029,663 discloses three anhydro derivatives each of 4-desacetylvinblastine, 4-desacetylvincristine and 4-desacetylleurosidine. These derivatives were prepared by the action of cold concentrated sulfuric acid on vinblastine, vincristine or leurosidine. Three different double bond isomers were formed and were designated as, in the case of VLB, 3',4'-anhydro 4-desacetyl VLB; 4',20'-anhydro 4-desacetyl VLB (isomer 2); and 4',20'-anhydro 4-desacetyl VLB (isomer 1). The 4',20' isomers are double bond isomers in which the 21'-methyl is either cis or trans (above or below the plane of the vinblastine molecule).
Potier, and Kutney and research groups associated with these two men have prepared a 3',4'-anhydrovinblastine by the use of a Polonovski fragmentation reaction involving reaction of an N.sub.b -oxide of catharanthine and vindoline in the presence of trifluoroacetic acid--see, for example, J.C.S. Chem. Comm. 670 (1975); British patent specification No. 1,536,407; Tetrahedron Letters, 1099, 3945 (1976); U.S. Pat. No. 4,144,237; Heterocycles, 3, 205, 639 (1975), 6, 905 (1977).
Functionalization of the double bond in 3',4'-anhydrovinblastine has proved difficult. Recently, Potier and his research group have reported the successful conversion of this compound (called by them .DELTA..sup.15'(20') -dehydrovinblastine) to vinblastine. This work is summarized in an article appearing a J.A.C.S., 101, 2243 (1979).
During the reaction of vinblastine, vincristine or leurosidine to yield the trio of double bond isomers known collectively as anhydrovinblastine, anhydrovincristine or anhydroleurosidine, a carbonium ion intermediate at C-4' is most probably formed. It is an object of this invention to utilize this transient carbonium ion in the preparation of novel 4'-derivatives of vinblastine; i.e., to contact the carbonium ion as it is formed with a specific reagent which reacts more rapidly with the carbonium ion to give new products than the alpha carbon (3' or 20') of the carbonium ion can lose a proton to yield a stable double bond. Other objects of this invention will become apparent from the following specification.